12alpha-halo-delta-pregnenes



United States Patc-ifili 12u-HALO-A -PREGNENES Josef Fried, New Brunswick, NJ, assignor to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed Jan. 8, 1957, Ser. No. 632,978

11 Claims. (Cl. 260397.3)

This invention relates to the synthesis of valuable steroids and has for its object the provision of: (I) an advantageous process of preparing steroids of the A pregnene (including the allopregnene, pregnadiene and pregnatriene) series having a IZa-halogen substituent, and of (II) certain steroids useful themselves as physiologically active steroids.

The process of this invention essentially comprises converting a steroid of the pregnane (including allopregnane, pregnene and pregnadiene) series having a 12mhalogen substituent and an llfi-hydroxy substituent into the corresponding M -derivative.

The compounds of this invention comprise the 120:- halo-A -steroids of the pregnene (including the allopregnene, pregnadiene and pregnatriene) series and, in particular, steroids of the general formula CHaY , oxide, sash as dimethyl sulfoxide,

Patented .Sept. 13, 1960,

or a glycol, as as di-. ethylene glycol].

Suitable starting materials utiliz'able in this process are disclosedin the US. applications of ,Iosef Fried and Josef E. He'rz, Serial No. 519,682, filed July 1, 1955;

' Serial No. 545,795, =filed November 8, 1955; and Serial No. 576,259, filed April 5, 1956. Representative members of said materials include: the 21 esters of- 12ahalohydrooortisones (e.g., l2a-fluorhydrooortisone 2 1 acetate); the 21-esters of l2a-halocorticosterones (e.g.,-

l2a-chlorocorticosterone 21-acetate) mamm lian dihydroxyprogesterones; 12u halo 1 lphydroxyprogesterones (e.-g., 12a-fiuoro-1lB-hydroxyprogesterone); the '21-es'ters of 12a halo} 1 dehydrohydrooortisones (e.g., 12a-fluoro-1-dehydrohydrocortisone 21-acetate);

; the 2l-esters of 12a-halo-l-dhydfocorticosterones; 12ahalo 1 dehydro 11?,17oc dihydroxyprogesterones; l2a-halo-l-dehydro-llfi-hydroxyprogesterones; the 21- esters of l2a-halo-6-dehydroliydrocortisones; 12a-halo- -dehydro-l'1/8-hydroXyprogesterones; the 2l-esters 'of 12a halopregnane ll,8,17u,21 triol 3,20 diones; 12a-halopregnane-1.1;3-ol-3,20-diones; and the 2-l-esters of IZd-halo-aIIopregnane-I1B,17a,21-triol-3,20-diones: j

The compounds of this invention are physiologically active steroids which possess progestational activity.

' '1 Hence, they can be used instead of progesterone, for

example, in the treatment of habitual abortion, being administered for such purpose 'in the same manner as progesterone with dosage adjusted for the activity of the particular steroid. a

The following examples illustrate the invention (;all temperatures being in centigrade):

EXAMPLE 1 12a-flubr0-9(11)-dehydroprogesterone A To a "solution of :lOO mg. of 12a-fiuoro-11B-hydroxyprogesterone in 2 ml. of dimethylformamide is added 0.2 ml. of pyridine and 0.2 ml. of methanesulfonyl chloride and the resulting mixture heated at 80 for hour. After cooling to room temperature, ice-water is added and the resulting suspension extracted with chloroform. The chloroform extract is washed with dilute sulfuric acid, sodium bicarbonate and water, dried over sodium sulfate and evaporated to dryness'in vacuo.

V The residue (about 100 mg.) is dissolved in 8 ml. benzene drogen or a-hydroxy; and Y is hydrogemwhydroxy or H These compounds are prepared interacting mifceiresponding llfl-hydroxy derivativeswith an organic. sulfonating agent, such as a lower alkane sulfonylhalide (e.g., mesyl chloride) or' arhmat'ie "sulfonyl halide -i losyl e i l, and etsaaiec ewsu h-a p'yi-idine. The reaction is preferablyconducted-again elevated temperature (e.g., a temperature in the range of about 50 C to about 100 C.) in the presence of an organic solvent of high polarity [e.g., a di(lower alkyl)-(1ower alkanoyl)amide, such as N,N-dimethylformamide or diethyl-acetamide, a di(lower alkyl)sulfand 8 ml. hexane and the solution chromatographed on 2 grams of acid-washed alumina. Benzene-hexane 1:1 (400 ml.) elute's crystalline material (about 60 mg.) which after recrystallization from acetone-hexane furnishes pure 12afluoro-9( ll)-dehydroprogesterone of the following properties: M.P.' about 144-1452 [oc] +205 (c., 0.63 in CHCl I L xii- 237 III/4 (e=.17,400); 1552 5.83, 5.99, 6.10, 6119 Analysis.Calcd. for 0, 11, 0 (330.42) C, 76.33? H, 8.23. Found: C, 76.l8;H, 8.15.

In a similar manner, when -12a-chloro-1.1,B-hydroxyprogesterone is substituted for the l2a-fiuoro-11p-hydroxyprogesteroneip the procedure of Example 1, 12achloro9( 1 1 -dehydropr ogesterone is obtained.

EXAMPLE 2 1 2 oz-fluoro-M' (1 1 -pfegnad ta e-I 7 a,21 -d i0l-3 ,2 O-dione 21 acetate Following the procedure of Example 1, but substituting l2ot-fluorohydrocortisorie" Q I-acetate for the 12mfluoro-l15-hydroxyprogesterone, there is obtained in good yield 12a-fluoro-A -pregnadiene-l7a,2l-diol- 3,20-dione 21-acetate.

In the same manner, by substituting IZu-bromohydrooortisone 12-acetate and 12a-chlorohydroeortisone 21- acetate for the l2a iiuoro llfi-hydroiiyprogesterone in I y the procedure of Example 1, '12a-bromo-A -pregnadiene-17a,21-diol-3,20-dione 21-acetate and l2a-chloro- Afrt ha a nel r lrfl -3.2 ll-aqeta mm obtained, respectively.

.EXAMPLE 3' I I, IZa-flubrO-A pregnadiene-l 70:,21 -diol-320 -di0ne A suspension of lOO mg. of 12a-fluoro-A w -pregnadiene-l7d,21-diol-3,20-dione ZI-acetate in 2 ml. of 0.27 N perchloric acid in'methanol is shaken at room temperature for 16 hours. Water'is added and the'methanol removed in vacuo; The'resultant crystals'are filtered, washed with dilute sodium acetate solution'and water, dried and 'recrystallized from 95% ethanol. 7 I j 3 In a similar manner, other ZI-es'ters canbe converted to the free 2l-hydroxyl derivatives.

EXAMPLE .4

1 When 12a-fluoro-l-dehydrohydrocortisone ZI-acetate is Substituted for the 12a fluoro-1 lfi-hydroxyprogesterone in Example 1, 12mfluoro-A -pregnatriene-l7a,21;diol- 3,20-dione 21 -acetateis produced.

- Similarly, 12m-chloro-l-dehydrohydrocortisone' 21-acewherein X is halogen, Z isselected from the group con} sisting of hydrogen'and nz-hydroxy, and Y is selected from terone in the procedure of Example 1, there is obtained 12a1fluoro-1 7a-hydroxy-9 1 1 -dehydroprogeste'rone.

Similarly, Ila-ChlQI'O-llfifl'la: dihydroxyprogesterone and IZa-bromQ-I1B,l7 }dihydroxyprogesterone yield 12':- chloro-l7m-hydroxy 9( l 1)-dihydroprogesterone and-- 12abromo-l7a-hydroxy-9( l1 -dehydroprogesterone, respec: tively. f i

EXAMPL-Ed the group consisting of hydrogen, hydroxy and acyloxy, wherein the acyl radical is that of a hydrocarbon carboxylic acid of less'than ten carbon atoms.

2. 12a-halo-9(-1 1') -dehydroprogesterone.

3. 12oc-flu01'0-9( 11)-dehydroprogesterone.

4. A 21-ester of 12a-halo-A -pregnadiene-l7a,21- diol-3,20-dione with a hydrocarbon carboxylic acid of less than ten carbon atoms.

5. 12a fluoro-A -pregnadiene-17a,21-diol-3,20 dione 21-acetate.

6. A 21-ester of 12a-fluoro-A -pregnatrienel7a, 2l@diol -3,20-dione with a hydrocarbon carboxylic acid of lessthanten carbon'atoms; 7 1' 7. '12u-fluoro-A -pregnatriene-l7a,2l-diol-3,20-dione 21-aceta-te. V 7 f 8. 12a-halo-17a-hydroxy-9(ll)-dehydroprogesterone.

-10. An ester of '1Za-halo-A pregnadiene-Z1-01-3, 20-dione with a hydrocarbon carboxylic acid of less than ten carbon'atoms. '11. -12a-fluoro-A -pregnadiene-2l-ol-3,20-dione 21 acetate.

References Cited the file of this patent i I UNITED STATES PATENTS] 2,628,240 Levinet a1.; ;Feb.- 10; 1953' 2,649,402 Murray et al.- Aug. 18, 1953 2,662,854 I Miescher et al. Dec. 15, 1953 2,769,825 Schneider et al Nov. 6, 1 956 2,782,211 Wettstein et 1 Feb. 19,195? 2 ,814,629 'Fried et al., Nov. 26, 1957 ,V24, 91 4,545 Herz t'al Nov. 2t, 1952 s 1 OTHER REFERENCES"; Fieser and Fieser: Natural Products Related: to Phen v anthrene; 3rd Edition (-1949), pages 242 454, 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS OF THE GENERAL FORMULAE 